Human Multidrug Resistance Gene Research Articles

Cerium-Encapsulated SbIII-SeIV-Templating Polyoxotungstate for Electrochemically Sensing Human Multidrug Resistance Gene Segment.

A tower-like SbIII-SeIV-templating polyoxotungstate [H2N(CH3)2]12Na7H3[Ce0.5/Na0.5(H2O)5]2[SbSe2W21O75]2·50H2O (1) was synthesized, whose skeleton is assembled from two prolonged lacunary Dawson [SbSe2W21O75]13- units and two [Ce0.5/Na0.5(H2O)5]2+ linkers. The uncommon [SbSe2W21O75]13- unit can be viewed as a combination of one [SeW6O21]2- group grafted onto a trivacant Dawson [SbSeW15O54]11- subunit. The conductive composite 1-Au@rGO containing 1, gold nanoparticles, and reduced graphene oxide (rGO) was conveniently prepared, using which the 1-Au@rGO-based electrochemical genosensor was constructed for detecting human multidrug resistance gene segment. This work enriches structural types of dual-heteroatom-inserted polyoxometalates and promotes the application of polyoxometalates in genosensors.

The Influence of MDR1 Expression Regulated by miR-138 through TRPS1 Signaling Pathway on Multidrug Resistance of Osteosarcoma and Formation of Bacterial Infection Biofilm.

This study was to investigate the effect of microribonucleic acid (mi-RNA) on the resistance of human multidrug resistance gene 1 (MDR1) to osteosarcoma through the Trico-nasal finger syndrome 1 (TRPS1) pathway, as well as the effect of mi-RNA on biofilm formation. For this purpose, firstly, the expression of MDR1 and TRPS1 in osteosarcoma cells was detected by quantitative polymerase chain reaction (qPCR) technology. Moreover, the clinical paraffin sections of osteosarcoma cells were collected to explore the correlation between MDR1 and TRPS1. Then, both the MG-38 cells expressing and not expressing miR-138 were expanded. Afterward, a plasmid with a full-length clone of the TRPS1 antibody was applied to transfect the cells. Besides, Q-OCR was employed to detect the expression of TRPS1 and MDR1, and the expression of TRPS1 protein and P-glycoprotein (P-gp) was detected by Western blot (WB). The MTT method was adopted to detect the changes in the median lethal dose of doxorubicin and cisplatin in cells from each group. The well plate was used to establish an in vitro bacterial infection biofilm model, and the above two transfected cells were added during the model establishment process. Moreover, the formation of biofilm in the two groups was observed. The result of the paraffin biopsy was 33% (25/75) of mi-RNA, the positive rate of TRPS1 was 18.6%, and the Pearson correlation coefficient of the two was 0.477. Under mi-RNA interference, the TRPS1 and MDR1 of the three system cells were sharply reduced, and the trend of changes between the two was the same. The tolerance of the mi-RNA interference group to doxorubicin, cisplatin, paclitaxel and 5-fluorouracil decreased steeply, and the median lethal dose dropped, while the non-mi-RNA interference group showed the opposite trend. In addition, the number of colonies in the interference group was less sharp than that of the control group and the non-mi-RNA interference group. The conclusion was that mi-RNA could control the expression of MDR1 through the TRPS1 pathway, thus affecting the multi-drug resistance of osteosarcoma and also influencing the formation of bacterial biofilms.

MDR1 Haplotypes and G2677T/A Polymorphism Predict Imatinib Response in Tunisian Patients with Chronic Myeloid Leukemia

Background: The role of human multidrug resistance gene (MDR1) SNPs in the interindividual variability of imatinib mesylate (IM) response has received considerable attention. We aimed to study the association between SNPs of the MDR1 gene (C1236T, G2677T/A, C3435T) and IM response in chronic myeloid leukemia (CML) patients. Method: A retrospective case-control study was conducted on 48 patients with CML undergoing IM therapy. All patients were genotyped using PCR-RFLP method. Results: The genotype and allele frequencies of C1236T and C3435T were not significantly different between CML patients responders and non-responders to IM (p > 0.05). The frequencies of 2677T allele and 2677TT genotype were significantly increased in CML patients IM responders which as compared with IM non-responders (50% vs 26.9%, p = 0.013 and 27.3% vs 3.8%, p = 0.029 respectively). Whereas the 2677AA genotype and CAC haplotype were found only in CML patients IM non-responders (15.4%). Conclusion: Pretreatment genotyping of G2677A/T appears to be useful for predicting IM resistance, which may allow the best choice of drug treatment for CML patients.

Engineered gene networks enable non‐genetic drug resistance and enhanced cellular robustness

Drug resistance complicates the treatment of cancer and infectious diseases, and often arises from the elevated expression of a gene that neutralises or reduces drug activity. To investigate this and other expression-based mechanisms of drug resistance, the authors engineered a set of gene regulatory networks in the eukaryotic model organism Saccharomyces cerevisiae to control a homologue of the cancer-related human multidrug resistance gene MDR1. Using this system, they explored experimentally how different gene regulatory network features, also called genetic network motifs, contribute to gene expression dynamics and cellular fitness. They observed that coherent feedforward and positive feedback motifs enable rapid and self-sustained activation of gene expression, and enhance cell survival in the presence of a cytotoxic drug. These observations underscore that genetic network motifs can be critical for drug resistance and that genetic network engineering can be used to enhance cellular tolerance to cytotoxins or other environmental stresses.

Regulatory effect of resveratrol and prednisolone on MDR1 gene expression in acute lymphoblastic leukemia cell line (CCRF-CEM): An epigenetic perspective.

Chemotherapy is the most common method to treat leukemia as well as other types of human cancers. However, drug resistance has remained as the main challenge against the efficacy of treatments. Furthermore, having various adverse effects, chemotherapy drugs are becoming replaced by natural modalities for cancer therapy. In this regard, herbal components such as resveratrol and prednisolone have been identified to sensitize the leukemic cells to programmed cell death through a set of complex processes. In this study, we have examined DNA methylation on the human multidrug resistance gene 1 (MDR1) as a well-known marker for cellular drug resistance. We evaluated the effect of resveratrol and prednisolone on DNA methylation patterns of MDR1 gene promoter in the CCRF-CEM cell line as a representative for acute lymphoblastic leukemia. The study was aimed to clarify whether the MDR1 gene expression is regulated via DNA promoter methylation as a potential underlying mechanism, following exposure to resveratrol and prednisolone. Our data revealed that despite a strong influence to down-regulate the MDR1 expression, Resveratrol and Prednisolone did not alter the methylation pattern, suggesting other regulatory mechanisms in controlling the MDR1 expression in CCRF-CEM cell line. Unchanged status of DNA methylation of MDR1 gene may suggest that Resveratrol and Prednisolone causes the gene expression changes through a distinct mechanism which requires further studies to be understood. A more detailed understanding of the mechanisms beyond the regulation of the genes involved in cancer formation will help to design novel therapeutic strategies to fight the human cancers.

An electrochemical DNA biosensor based on nitrogen-doped graphene/Au nanoparticles for human multidrug resistance gene detection

Multidrug resistance (MDR) has become a major obstacle to the adequate treatment of cancer patients; thus, there is an urgent need for exploring new strategies for early diagnosis of MDR in clinic. Here, we report a novel electrochemical biosensor based on nitrogen-doped graphene nanosheets functionalized with Au nanoparticles (N-G/Au) for sensitive and selective DNA detection. The highly conductive nanocomposite layer was characterized by using scanning and transmission electron microscopy, X-ray photoelectron spectroscopy, and cyclic voltammetry. DNA with thiol groups at the 5′ end was immobilized on the N-G/Au surface via the strong Au–S bond. Differential pulse voltammetry was applied to monitor the target DNA hybridization event using methylene blue as an electrochemical indicator. Under optimal conditions, the biosensor could detect target DNA down to 3.12×10−15M with a linear range from 1.0×10−14 to 1.0×10−7M, showing high sensitivity. Further, the sensing strategy was successfully used for detecting MDR1 DNA in real clinical samples. These results will aid in developing a new portable detection system for MDR that will allow effective diagnosis in the early stages of related cancer.

Externalization of phosphatidylserine via multidrug resistance 1 (MDR1)/P-glycoprotein in oxalate-treated renal epithelial cells: implications for calcium oxalate urolithiasis.

We investigated the possible involvement of multidrug resistance protein 1 P-glycoprotein (MDR1 P-gp) in the oxalate-induced redistribution of phosphatidylserine in renal epithelial cell membranes. Real-time PCR and western blotting were used to examine MDR1 expression in Madin-Darby canine kidney cells at the mRNA and protein levels, respectively, whereas surface-expressed phosphatidylserine was detected by the annexin V-binding assay. Oxalate treatment resulted in increased synthesis of MDR1, which resulted in phosphatidylserine (PS) externalization in the renal epithelial cell membrane. Treatment with the MDR1 inhibitor PSC833 significantly attenuated phosphatidylserine externalization. Transfection of the human MDR1 gene into renal epithelial cells significantly increased PS externalization. To our knowledge, this study is the first to show that oxalate increases the synthesis of MDR1 P-gp, which plays a key role in hyperoxaluria-promoted calcium oxalate urolithiasis by facilitating phosphatidylserine redistribution in renal epithelial cells.

Direct genotyping of C3435T single nucleotide polymorphism in unamplified human MDR1 gene using a surface plasmon resonance imaging DNA sensor.

Optical genotyping of C3435T single nucleotide polymorphisms (SNPs) in unamplified human multidrug resistance (MDR1) gene was here performed by a surface plasmon resonance imaging (SPRi) dual-targeting DNA assay, allowing its selective detection down to 0.18 fM of the whole genomic DNA. The result was achieved by the combination of the rational selection of the DNA probe and an optimized sample pretreatment (i.e., ultrasound fragmentation and thermal denaturation). Some assay developments and tunings were reported in a previously published research, but here, for the first time, the biosensor reliability and its analytical performance were directly tested on the unamplified human DNA extracted from lymphocytes. The assay resulted to be able to differentiate among all the possible genotypes of C3435T (homozygote and heterozygote) in the diluted genomic samples using a label-free approach and by bypassing the classical PCR amplification of the target sequences. Moreover, the reusability of the DNA-based chip allowed up to 40 subsequent measuring cycles, opening new horizons in multi-SNP genotyping based on cheap and daily routine clinical monitoring by optical biosensing.

Periplocymarin is a potential natural compound for drug development: highly permeable with absence of P‐glycoprotein efflux and cytochrome P450 inhibitions

Periplocymarin, a cardiac glycoside isolated from Periploca sepium (P. sepium) and Periploca graeca (P. graeca), is a potential anti-cancer compound. The aim of the study was to investigate the potential for periplocymarin to interact with P-glycoprotein (P-gp) and to inhibit cytochrome P450s known to be expressed in the human small intestine. The in vitro and in situ permeability of periplocymarin were studied using Madin-Darby canine kidney (MDCK-II-WT) cells transfected with or without the human multidrug resistance (MDR1) gene and the single-pass perfused rat intestinal model. The cell system exhibited high functional activity and a net efflux ratio (NER) of 4.32 after transport of Rhodamine 123 (R123) (the P-gp substrate). Periplocymarin is highly permeable (Papp > 10 × 10(-6) cm/s; Peff(rat) > 5.09 × 10(-5) cm/s) and independent of P-gp influences. The NER at 100 μm periplocymarin (0.8) was unchanged in the presence of cyclosporine A (a non-specific P-gp inhibitor) (0.82). In the single-pass intestinal model, the Peff (rat) of 5 µg/ml periplocymarin (5.490 × 10(-5) cm/s) did not change in the presence of cyclosporine A (5.394 × 10(-5) cm/s). In the R123-inhibition assay, periplocymarin did not competitively inhibit P-gp. The inhibitory potential of periplocymarin on cytochrome P450 (CYP450s) was also studied. Periplocymarin (5, 50 μm) did not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6 or CYP3A4. Thus, periplocymarin is unlikely to encounter drug-drug interactions with P-gp and CYP450s. Periplocymarin could be taken forward for further studies in drug development to test bioavailability, Phase II enzyme interactions and additional transporter interactions.

Association of MDR1 gene polymorphism (G2677T) with imatinib response in Egyptian chronic myeloid leukemia patients

BackgroundDespite the excellent efficacy results of imatinib treatment in CML patients, resistance to imatinib has emerged as a significant problem. Genetic variations in genes involved in drug transportation might influence the pharmacokinetic and metabolism of imatinib. The genotype of a patient is increasingly recognized in influencing the response to the treatment.AimTo investigate the genotype frequencies of single nucleotide polymorphisms (SNPs) G2677T in CML patients undergoing imatinib treatment to determine whether different genotype pattern of these SNPs have any influence in mediating response to imatinib.MethodsA total of 96 CML and 90 control samples were analyzed for the human multidrug resistance gene 1 (MDR1) gene polymorphism (G2677T) using polymerase chain reaction-restriction fragment length polymorphism technique.ResultsGenotype distribution revealed a significant lower frequency of TT genotype in CML patients and non-significant difference in the GG, GT genotype frequencies between patients and controls (P = 0.004, 0.138, 0.210, respectively). GG genotype was significantly higher in chronic phase (P = 0.046), while GT genotype was significantly higher in Blastic crisis phase (P = 0.002). There was a significant difference in genotype frequency of G2677T among patients showing response and resistance to imatinib in chronic phase (P = 0.02). TT genotype was associated with complete hematological response (P = 0.01), complete cytogenetic response (P < 0.001), and better molecular response with a significant association (P < 0.001). GT genotype was associated with partial hematological response (P = 0.01) and minor cytogenetic response (P < 0.001). Optimal and suboptimal responses were observed for patients with TT genotype (P = 0.003). Failure of drug response was associated with GT genotype (P = 0.02); however, GG had no association with drug response. Multivariate analysis considered GT genotype as independent risk factor for resistance (P = 0.037), while TT genotype as protective factor against resistance to imatinib (P = 0.008).ConclusionDetermination of MDR1 polymorphisms (G2677T) might be useful in response prediction to therapy with imatinib in patients with CML.

AB1144 Influence the level of PGP activity (product of MDR1GENE) on the efficiency of basic therapy in children with juvenile idiopathic arthritis

BackgroundStudies of the MDR1 gene started from the early 80s of the XX century, when first studied protein expression Pgp-170. In 2000, for the first time it was found that...

Influence of ABCB1 genetic variants in breast cancer treatment outcomes

BackgroundTransportation of anticancer drugs such as anthracyclines across the membrane is regulated by P-glycoprotein encoded by the human multidrug resistance gene 1 (ABCB1). Polymorphisms in the ABCB1 gene (1236C>T, 2677G>T/A, 3435C>T) have been found to be associated with intrinsic and acquired cross resistance to these anticancer drugs. Therefore, the aim of this study is to evaluate the influence of ABCB1 gene polymorphisms in breast cancer treatment outcomes in terms of response and toxicity. MethodResponse to neo-adjuvant chemotherapy was evaluated in 100 patients while grade 2–4 toxicity was followed in 207 patients, who had undergone FEC/FAC chemotherapy. Genotyping for ABCB1 polymorphisms was done by PCR-RFLP. Chi square and logistic regression analyses were used to calculate Odd's ratio using SPSS ver 17.0. A meta analysis was also performed using Comprehensive Meta Analysis Ver 2. ResultsIn response evaluation, 1236C>T polymorphism was significantly associated with treatment response for CT genotype [OR=5.17(1.3–20.2), P=0.018] and in dominant model (CC vs CT+TT) [OR=4.63(1.25–17.0), P=0.021]. In the toxicity group, the T allele of 1236C>T was associated with grade 2–4 tocxicity [OR 1.48(1.00–2.20), P=0.049] and the association was also significant in the recessive model [OR 1.88(1.05–3.39), P=0.033]. For other two SNPs 2677G>T/A and 3435C>T no association was seen with either treatment response or grade 2–4 toxicity. In meta analysis, no overall association was found. ConclusionIn our study, significant association was seen for ABCB1 1236C>T polymorphism with treatment response. The meta analysis did not show overall association with treatment outcomes.

MDR1 polymorphisms (G2677T and C3435T) in B-chronic lymphocytic leukemia

The human multidrug resistance (MDR1) gene encodes P-glycoprotein, which affects the pharmacokinetics of many drugs. We investigated whether common MDR1 single-nucleotide polymorphisms (C3435T and G2677T) affect predisposition to B-chronic lymphocytic leukemia (B-CLL). Genotyping was performed in 65 patients with CLL and in 70 controls using polymerase chain reaction—restriction fragment length polymorphism. We observed a higher frequency of carriers of 3435CT gene among B-CLL patients as compared to normal individuals (58.5 vs. 22.9 %, p = <0.001). The genotype 3435CT was associated with B-CLL [odds ratio = 4.8, 95 % confidence interval = 2.3–10.0]. Moreover, patient and control groups did not differ significantly regarding the MDR1 genotype (G2677T). Furthermore, no correlation was shown between the MDR1 (3435 or 2677) genotypes and clinical and laboratory data of patient group. These data indicate that MDR1 C3435T single-nucleotide polymorphism may carry an increased risk of developing B-CLL.

Lack of association between MDR1 C3435T polymorphism and chemotherapy response in advanced breast cancer patients: evidence from current studies

The transmembrane transport of anticancer drugs is mainly regulated by P-glycoprotein encoded by the human multidrug resistance gene 1 gene (MDR1). Since there were controversies regarding the association between MDR1 C3435T polymorphism and response to chemotherapy among patients with advanced breast cancer, a meta-analysis of the link was conducted. A total of 7 studies consist of 464 advanced breast cancer patients relating MDR1 C3435T polymorphism to the response of chemotherapy were included in this meta-analysis. The main analysis revealed a lack of association between the MDR1 C3435T and response to chemotherapy, with odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) of 1.37 (95% CI: 0.78-2.40), 1.17 (95% CI: 0.69-2.01), 1.18 (95% CI: 0.76-1.84) and 1.61 (95%CI: 0.70-3.68) for homozygous comparison, heterozygous comparison, dominant model and recessive model, respectively. The subgroup analysis by ethnicity did not change the pattern of results, with ORs of 0.99 (95% CI: 0.11-9.07), 0.68 (95%CI: 0.29-1.60), 0.81 (95%CI: 0.36-1.85) and 1.51 (95% CI: 0.77-2.96), in homozygous comparison, heterozygous comparison, dominant model and recessive model, respectively in Caucasian, and 1.50 (95% CI: 0.75-3.03), 1.72 (95% CI: 0.85-3.47), 1.59 (95% CI: 0.90-2.80) and 2.29 (95% CI: 0.51-10.35), respectively in Asian. The available evidence indicates that MDR1 C3435T polymorphism cannot be considered as a reliable predictor of response to chemotherapy in patients with advanced breast cancer.

Multi-drug resistance 1 genetic polymorphism and prediction of chemotherapy response in Hodgkin's Lymphoma

BackgroundThe human multi-drug resistance gene (MDR1), which encodes the major trans-membrane transporter P-glycoprotein (P-gp), was found to be associated with susceptibility to cancer and response to chemotherapy. The C3435T Polymorphism of MDR1 gene was correlated with expression levels and functions of P-gp. Here, we studied the association between MDR1 C3435T polymorphism and susceptibility to Hodgkin lymphoma (HL) and patient's response to ABVD chemotherapy regimen.Methodsa total of 130 paraffin embedded tissue samples collected from HL patients were analyzed to identify the C3435T polymorphism. As a control group, 120 healthy subjects were enrolled in the study. The C3435T Polymorphism was genotyped by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. Data analysis was carried out using the statistical package SPSS version 17 to compute all descriptive statistics. Chi-square and Fisher exact tests were used to evaluate the genotype distribution and allele frequencies of the studied polymorphism.Resultsthese studies revealed that the frequency of T allele was significantly higher in HL patients compared to the controls (P < 0.05). In addition, the frequency of CT and TT genotypes were also significantly higher in HL patients compared to the controls (P < 0.05). No association between C3435T polymorphism and response to ABVD was detected among HL patients (P > 0.05).Conclusionsthese results suggest that MDR1 C3435T polymorphism might play a role in HL occurrence; however this polymorphism is not correlated with the clinical response to ABVD.

Polymorphisms and haplotypes in multidrug resistance 1 gene are not associated with chronic lymphocytic leukemia susceptibility and prognostic parameters of chronic lymphocytic leukemia in Chinese population

The human multidrug resistance (MDR1, ABCB1) gene encodes P-glycoprotein (P-gp), which affects the pharmacokinetics of many drugs. Here, we investigated whether common MDR1 single nucleotide polymorphisms (SNPs) (C1236T, C3435T, and G2677T/A) affect predisposition to chronic lymphocytic leukemia (CLL). Genotyping was performed in 150 patients with CLL and 117 controls using polymerase chain reaction (PCR)-based assays. Haplotypes were inferred using the PHASE algorithm. We found comparable allele and genotype frequencies among patients with CLL and controls. Moreover, patient and control groups did not differ regarding MDR1 haplotype distribution (p = 0.97). Furthermore, no correlation was shown between the MDR1 1236, 3435, or 2677 genotypes and Binet stage, unmutated immunoglobulin heavy-chain variable region (IGHV) status, CD38 expression, ZAP-70 expression, and p53 deletion. In conclusion, our results do not support a major influence of MDR1 variants on the risk of CLL, and these genomic polymorphisms are not associated with clinical prognostic factors in Chinese patients with CLL.

ATP-binding cassette transporters in primary central nervous system lymphoma: Decreased expression of MDR1 P-glycoprotein and breast cancer resistance protein in tumor capillary endothelial cells

Most tumors in the central nervous system are drug resistant partly because of the presence of the blood-brain barrier (BBB) between circulating blood and tumor tissues. Primary central nervous system lymphoma (PCNSL) is one of the exceptions, as it is highly sensitive to high-dose methotrexate (MTX)-based chemotherapy. The aim of this study was to evaluate the BBB function of tumor capillary endothelial cells in PCNSL. Expression of three major drug efflux transporters that belong to the ATP-binding cassette (ABC) superfamily, P-glycoprotein encoded by the human multidrug resistance gene (MDR1 Pgp; ABCB1), breast cancer resistance protein (BCRP; ABCG2), and multidrug resistance-associated protein 1 (MRP1; ABCC1), was evaluated. Immunohistochemistry was performed in capillary endothelial cells of 30 tumor areas from 22 PCNSL cases and compared with that of 30 gliomas. The microenvironment around tumor capillaries was assessed by examining the distribution of astrocytes and by counting the number of macrophages and T-cells, the principal cytokine producers. In PCNSL, expression of MDR1 Pgp and BCRP in tumor capillary endothelial cells was decreased in 63 and 93% of tumor areas examined, respectively, and these reduction levels differed significantly from those of gliomas (P<0.05). When the PCNSLs were further segregated by way of infiltration of tumor cells into three patterns (dense, perivascular and sparse), decreased MDR1 Pgp and BCRP in tumor capillary endothelial cells were much more prominent in dense and perivascular patterns. In all tumors and non-tumor areas of the brain, MRP1 was undetected on capillary endothelial cells. Assessment of the microenvironment around the tumor capillaries suggested that dissociation from astrocytes and infiltration of macrophages and T-cells was involved in the down-regulation of MDR1 Pgp and BCRP in capillary endothelial cells. In conclusion, we report that expression of the major ABC transporters of the BBB, MDR1 Pgp and BCRP, decreases in tumor capillary endothelial cells of PCNSL. Thus, decreased expression may permit delivery of chemotherapeutic agents to the tumor tissues.

A Novel MDR1 GT1292-3TG (Cys431Leu) Genetic Variation and Its Effect on P-glycoprotein Biologic Functions

P-glycoprotein (P-gp) is a membrane-bound transporter protein that is encoded by the human multidrug resistance gene MDR1 (ABCB1). P-gp recognizes a wide range of xenobiotics, is pivotal in mediating cancer drug resistance, and plays an important role in limiting drug penetration across the blood-brain barrier. MDR1 genetic variation can lead to changes in P-gp function and may have implications on drug pharmacokinetics. We have identified a novel MDR1 (GT1292-3TG) (Cys431Leu) genetic variation through systematic profiling of subjects with leukemia. The cellular and transport function of this variation was investigated with recombinant human embryonic kidney cells expressing MDR1. Compared with the wild type, MDR1 (GT1292-3TG) recombinant cells exhibited a lower drug resistance phenotype for a panel of chemotherapeutic agents. When compared with wild type, MDR1 (GT1292-3TG) recombinant cells exposed exhibited a 75% decrease in IC₅₀ for doxorubicin (162.6 ± 17.4 to 37.9 ± 2.6 nM) and a 50% decrease in IC(50) for paclitaxel (155.7 ± 27.5 to 87.7 ± 9.2 nM), vinblastine (128.0 ± 15.9 to 65.9 ± 5.1 nM), and vincristine (593.7 ± 61.8 to 307.3 ± 17.0 nM). The effects of the Cys431Leu variation, due to MDR1 (GT1292-3TG) nucleotide transition, on P-gp-dependent intracellular substrate accumulation appeared to be substrate dependent where doxorubicin, vinblastine, and paclitaxel exhibit an increased accumulation (p < 0.05), while verapamil and Hoechst33342 exhibit a decreased intracellular concentration compared with wild type (p < 0.05). Collectively, these data suggest MDR1 (GT1292-3TG) variation of P-gp may reduce drug resistance and that subjects with this genotype undergoing chemotherapy with drugs that are transported by P-gp could potentially be more responsive to therapy than those with MDR1 wild-type genotype.

Multidrug resistance gene (MDR1) polymorphisms correlate with imatinib response in chronic myeloid leukemia

The human multidrug resistance gene (MDR1, ABCB1) codes for P-glycoprotein (P-gp) that affects the pharmacokinetics of many drugs. MDR1 single nucleotide polymorphisms (SNPs) are associated with drug clearance. Imatinib is a substrate of P-gp-mediated efflux. We investigated the MDR1 T1236C, G 2677T/A, and C3435T polymorphism in 52 patients with chronic myeloid leukemia treated with imatinib. The distribution of MDR1 1236, 2677, or 3435 genotypes was significantly different between the resistance patients and sensitivity patients. The resistance incidence correlated with the number of T alleles at locus 1236 and 3435. Resistance was higher for patients homozygous for the 1236T allele when compared to patients with CT/CC genotype groups (75% vs. 31.3%, P = 0.004). For the G2677T/A polymorphism, a better complete cytogenetic remission was observed for patients with genotype AG/AT/AA, when compared to other genotype groups (TT/GT/GG, P = 0.02). Patients with 3435 TT/CT genotypes showed a higher resistance when compared with patients with CC genotype (59.4% vs. 25%, P = 0.023). In conclusion, determination of 1236T, C3435T, and G2677T MDR1 polymorphisms might be useful in response prediction to therapy with imatinib in patients with CML.

Association of the colorectal cancer and MDR1 gene polymorphism in an Iranian population

The human multidrug resistance (MDR1) gene product P-glycoprotein is highly expressed in intestinal epithelial cells, where it constitutes a barrier against xenobiotics, bacterial toxins, drugs and other biologically active compounds, possibly carcinogens. In this study, an association of MDR1 gene polymorphism and the occurrence of colorectal cancer were evaluated. In this case-control-designed 118 unrelated colorectal cancer and 137 sex-and-ages matched healthy controls were enrolled. The C3435T MDR1 gene polymorphism was identified using the polymerase chain reaction-restriction fragment length polymorphism method. Significantly increased frequencies of the 3435T allele and the 3435TT were observed in patients with colorectal cancer compared with controls (P = 0.03; OR, 95% CI; 1.46 for 3435T allele and P = 0.003; OR, 95% CI; 2.2 for 3435TT genotype). In contrast, frequency of genotype TT was significantly higher in controls compared to colorectal cancer (P = 0.006; OR, 95% CI; 0.49 for TC genotype). In this study suggest that C3435T MDR1 polymorphism has an association with colorectal cancer. The results support that the presence of allele C results in decreased susceptibility to colorectal cancer.